Hyperlipemia, diabetes, and hypertension have been called risk factors in arteriosclerotic diseases such as ischemic heart diseases. Hyperlipemia means a condition in which lipids such as cholesterol increase abnormally in the blood. There are three types of hyperlima depending on the cause. One is primary hyperlipemia which results from hereditary abnormality of enzymes and proteins involved in metabolism of low density lipoprotein (LDL) and lipoprotein receptors. The second is second hyperlipemia which results from various diseases or the administration of some drugs. The third is non-genetic hyperlipemia based on supernutrition.
Lipids taken from meals are absorbed in the small intestine through the action of bile acid and are secreted into the blood as chylomicron via lymph vessels. The triglyceride (TG) moiety of secreted chylomicron is catabolized to free fatty acids by lipoprotein lipase (LPL), which is found in capillary wall, and converted into cholesteryl ester (CE)-rich chylomicron remnants, which are taken up to the liver via the chylomicron remnant receptor. In the liver, chylomicron remnants taken up and/or free fatty acids are further converted into TG and the such as by enzymes such as acyl CoA synthetase (ACS). The resulting products are then associated with apolipoprotein B synthesized on rough endoplasmic reticulum to form very low density lipoprotein (VLDL). VLDL is transferred to the Golgi apparatus and undergoes modification. The modified VLDL is secreted extracellularly to become intermediate density lipoprotein (IDL) through action of LPL. The resulting IDL is converted to LDL by HTGL (heptatic lipase). Thus, lipids are distributed to peripheral tissues.
It has been indicated that, upon the formation of chylomicron in the small intestine and VLDL in the liver, proteins having TG and CE-transferring activity were present in microsomal fractions in the small intestine and the liver. In 1985, Wetterau et al. isolated and purified the protein, i.e., microsomal triglyceride transfer protein (MTP), from microsomal fractions in bovine liver (Wetterau, J. R. et al.: Chem. Phys. Lipids 38, 205-222 (1985)). However, MTP was not spotlighted in the field of clinical medicine until the cause of abetalipoproteinemia was reported to be the defect of MTP in 1993. This disease is characterized by the near absence of apolipoprotein B in serum but a lack of abnormality in apolipoprotein B-related genes. Serum cholesterol is below 50 mg/dl, and serum triglyceride levels are extremely low. Another characteristic of the disease is that lipoproteins containing apolipoprotein B such as chylomicron, VLDL, and LDL are completely absent in the blood. These findings indicate that MTP is a necessary protein for conjugation of apolipoprotein B with TG and CE, i.e., for forming VLDL and chylomicron, and plays a fundamental role in secreting these lipoproteins.
Since lipids are by nature insoluble in water, they associate with a hydrophilic protein called apolipoprotein in the blood and are present as lipoproteins. VLDL, IDL, LDL and chylomicron, which are involved in hyperlipemia, are all lipoproteins.
MTP is present in microsomal fractions in hepatocytes and epithelial cells of the small intestine and is responsible for intracellular transfer of TG and CE. Accompanying the synthesis of apolipoprotein B (apolipoprotein B 100 in the liver and apolipoprotein B48 in the small intestine), TG and CE become associated with their corresponding apolipoproteins through the transferring action of MTP to form VLDL or chylomicron in the liver and small intestine. As a result, these lipoproteins are secreted extracellularly as VLDL from the liver and as chylomicron from the small intestine. MTP is necessary to assemble these lipoproteins. Thus, formation of lipoproteins can be inhibited by inhibiting MTP activity to thereby prevent transfer to lipids such as TG to apolipoproteins.
It has become apparent that LDL is intimately involved in the development of arteriosclerotic diseases in general. LDL penetrates the endothelium of blood vessels and is deposited in an intercellular matrix of the vessel wall. Oxidative degeneration occurring there triggers a series of inflammatory reactions induced by lipid peroxides and degenerated proteins to thereby cause invasion by macrophages and vascular smooth muscles, deposition of lipid, proliferation of cells, and increases in the intercellular matrix in blood vessel walls. Arteriosclerotic lesions are then formed. Thus, arteriosclerotic diseases can be prevented or treated by decreasing LDL.
As described above, it is possible to prevent formation of lipoproteins such as VLDL and LDL by inhibiting MTP activity. Therefore, TG, cholesterol, and lipoproteins such as LDL in the blood and lipids in the cells can be controlled by regulating MTP activity. Compounds having such activity are expected to become new drugs for preventing and treating not only hyperlipemia or arteriosclerotic diseases but also pancreatitis, obesity, hypercholesterolemia, hypertriglyceridemia, and the such as.
Recently, compounds with MTP-inhibitory activity have been reported.
For example, Eur. J. Biochem. 240, 713 to 720 (1996) discloses 4'-bromo-3'-methylmethaqualone as a compound having MTP-inhibitory activity. However, the literature neither discloses nor suggests compounds having such structures as those of the compounds of the present invention.
Unexamined published Japanese paten application (JP-A) Hei 6-38761 (EP 584446) discloses 2-[1-(3,3-diphenylpropyl)-4-piperidinyl]-2,3-dihydro-3-oxo-1H-isoindole hydrochloride as a compound with MTP-inhibitory activity. However, activity with such structures as those of the compounds of the present invention are neither disclosed nor suggested in the publication.
Furthermore, as a compound with MTP-inhibitory activity, JP-A-Hei 7-165712 (U.S. Pat. No. 5,595,872) discloses 2-(4-piperidyl)-2,3-dihydro-3-1H-isoindole compounds such as 2-[1-[2-(5H-dibenzo[a,d]cyclohepten-5-yl)ethyl]-4-piperidyl]-2,3-dihydro-3 -oxo-1H-isoindole, and WO 96/26205 discloses isoindole compounds such as 9-[3-[4-(2,3-dihydro-1-oxo-1H-isoindole-2-yl)-1-piperidyl]-propyl]-N-propy l9H-fluorene-9-carboxamide. However, none of these publications disclose or suggest compounds with such structures as those of the compounds of the present invention.
WO 96/40640 discloses biphenyl-2-carboxylic acid tetrahydroisoquinolin-6-yl amide derivatives such as 4'-trifluoromethyl-biphenyl-2-carboxylic acid [2-(1,5a,6,9,9a,9b-hexahydro-4H-dibenzofuran-4a-ylmethyl)-1,2,3,4-tetrahyd roiso-quinolin-6-yl]amide as an MTP-inhibitor. However, the publication neither discloses nor suggests compounds with such structures as those of the compounds of the present invention.
There are many reports showing compounds having the 3-piperidyl-4-oxoquinazoline structure similar to the compounds of the present invention.
For example, JP-A-Sho 53-38784 (U.S. Pat. No. 4,166,117) discloses N-substituted quinazoline compounds such as 1-[(2,6-dimethylphenoxy)-2-ethyl]-4-[4-oxo[3H]quinazolin-3-yl]piperidine as compounds with antihypertensive activity. However, the publication does not disclose compounds with structures such as those of the compounds of the present invention. Moreover, the publication neither discloses nor suggests that the compounds have MTP-inhibitory activity.
JP-A-Hei 8-151377 discloses quinazoline derivatives such as N-(2,6-dichloro-4-nitrophenyl)-4-(1,2,3,4-tetrahydro-1,6-dimethyl-2,4-diox oquinazolin-3-yl)-1-piperidine acetamide. However, the compounds disclosed in the publication show adenosine uptake inhibitory activity, and there is neither description nor suggestion that the compounds have MTP-inhibitory activity.
U.S. Pat. No. 4,364,954 discloses diphenyl propaneamine compounds such as 1-[1-[3-[bis(4-fluorophenyl)amino]propyl]-4-piperidyl]-1,3-dihydro-2H-benz imidazol-2-one. The compounds are disclosed as a therapeutic agent for schizophrenia, not as an MTP inhibitor as in the present invention. Furthermore, the publication neither discloses nor suggests compounds with structures such as those of the compounds of the present invention.
EP 802188 discloses that hetero-bonded phenylglycinol amides having a 4-oxoquinazonyl group are effective against atherosclerotic diseases. However, the publication neither discloses nor suggests compounds with structures such as those of the compounds of the present invention.